Overview: Recent evidence indicates that co-infection with HCV may negatively impact HIV disease progression and response to HAART. Almost 40 percent) of women enrolled in the Women's Interagency HIV Study (WMS) are co-infected with HCV affording a unique opportunity to study the effect of HCV on disease progression and response to HAART. We propose a two-part study that will consist of both retrospective and prospective evaluations utilizing repository samples and clinical information from 368 HIV+/HCV+ and 650 HIV+/HCV- women in WMS and 30 newly identified HAAKT-naive women. Hypotheses: We hypothesize that: i) HIV-1 infected women who are co-infected with HCV will have increased H N RNA levels, and more rapid CD4 decline and progression to AIDS than women who are HCV uninfected, and ii) after HAART, HCV viremia and extrahepatic replication will impair viral response to therapy and immune recovery. Aims: To address hypothesis I , we will determine the relationship between HCV infection and disease progression based on epidemiologic, clinical, virologic, and immunologic features of women in WIHS. Specifically we will: i) study the effect of plasma HCV RNA, quasispecies diversity, and genotype on HIV disease progression; ii) assess for extrahepatic replication in PBMCs and determine its relationship with HIV RNA level and stage of HIV disease; iii) establish if HCV viremia and extrahepatic replication are associated with immune activation, alterations in naive and memory CD4 and CD8 cells, and thymic output. To address hypothesis 2, we will: i) assess if plasma HCV RNA, genotype, quasispecies diversity and extrahepatic replication in PBMCs prior to HAART influence virologic and immunologic response after HAART; and ii) evaluate for early changes in HIV and HCV RNA and immune recovery following HAART in a group of intensively followed women. These studies will contribute to our understanding of the interaction of these viruses in a clinical setting and help to delineate populations of women who may benefit from specific antiviral therapies.